The long-term goal of this project is to develop novel targeted therapy for human pancreatic cancer (pancreatic ductal adenocarcinoma, PDA). PDA is a devastating disease with low survival rate and short survival time. The current systemic therapy has only marginal benefit to PDA patients. There is an urgent need for the development of effective and safe therapy for PDA. The loss of tumor suppressor (e.g., p53) and/or the overexpression of oncogenes (e.g., MDM2 and ?-catenin) have been linked to resistant to treatment and poor prognosis in PDA patients. The oncogene MDM2 is a negative regulator of p53 and has been suggested to be a valid molecular target for cancer therapy. Up to date, the majority of small molecule inhibitors (SMIs) of MDM2 have been designed to block the MDM2-p53 binding, reactivating the p53 function. However, the majority of PDA harbors mutant p53 and has high levels of MDM2; these MDM2 SMIs are expected to have low or no efficacy against PDA. Therefore, it is highly desirable to design novel MDM2 SMIs that have direct effects on MDM2 and exert their anticancer activity, independent of p53 status. Based on this new conceptual framework, the applicants have designed a series of novel, highly selective MDM2 SMIs, i.e. 1-aryl and 1- heteroaryl pyrido[b]indole derivatives and generated preliminary data to provide a basis for further development of the lead compounds as novel therapeutics for PDA treatment. These SMIs directly bind to MDM2, induce MDM2 degradation, inhibit cell growth, and induce apoptosis in PDA cells. One of the lead compounds, SP141, has significant in vitro activity, in vivo efficacy, and minimal host toxicity. When investigating its mechanisms o action, the applicants discovered a secondary target of SP141: inhibiting ?-catenin expression and its transactivation activity in PDA cells. In this proposal, the applicants will test the centrl hypothesis that SP141 is a novel effective and safe therapeutic agent for the treatment of human PDA and exerts its anti-PDA activity through targeting both MDM2 and ?-catenin. Four hypothesis-driven specific aims are proposed: 1) to demonstrate the in vivo efficacy of SP141 in various PDA models, including orthotopic, transgenic, and primary tumor-derived models; 2) to demonstrate that targeting MDM2 is the major mechanism of action for SP141-mediated anti-PDA activity; 3) to elucidate the role of ?-catenin inhibition in SP141- mediated anticancer activity; and 4) to characterize the pharmacological and toxicological properties of SP141 in PDA-relevant models. Upon completion of these proposed studies, the anticipated results will provide information on the therapeutic efficacy and safety of SP141 and the validation of the novel drug design strategy of targeting both MDM2 and ?-catenin in PDA. It is expected that this project will generate in a novel clinical candidate for PDA therapy, which would have a major impact on patient care and public health and that the mechanistic studies will shed more lights on the role of MDM2 and ?-catenin in PDA development, progression, and therapy.